Neuhauser Lecture - 2005 - Bruce Korf, MD

Bruce R. Korf, MD, PhD
Wayne H. and Sara Crews Finley Professor of Medical Genetics
Chair, Department of Genetics
The University of Alabama at Birmingham
Birmingham, Alabama

The neurofibromatoses are a set of genetically distinct disorders that are characterized by the development of tumors of the nerve sheath.  The current classification includes three disorders, NF1, NF2, and Schwannomatosis.   The hallmark lesion of NF1 is the neurofibroma, whereas that in NF2 and Schwannomatosis is the schwannoma.  Individuals with NF1 develop many additional clinical problems, including skeletal dysplasias, learning disabilities, and malignancy.  This talk will focus on NF1, highlighting current challenges in diagnosis and management, and the role that the radiologist is playing in helping to meet these challenges.

Diagnosis of NF1
The diagnosis of NF1 is based on clinical criteria that originated from an NIH consensus conference in 1987(1) and have subsequently been revised(2).  The criteria are listed in Table 1. An individual who fulfills these criteria can be confidently diagnosed as having NF1, but many of the features are age-dependent, causing diagnostic uncertainty in many children who present with multiple café-au-lait spots(3). 

Radiological approaches have been useful in establishing a diagnosis.  One criterion, optic glioma, requires imaging to be detected.  Skeletal dysplasia also requires radiological confirmation.   The presence of areas of enhanced T2 signal intensity has also been proposed as a diagnostic criterion for NF1, but the specificity of this finding has been questioned(4). 

The NF1 gene was identified in 1990, raising the possibility of offering genetic testing for the disorder.  The gene is large, however, and there is a wide diversity of mutations that are scattered throughout the gene.  As a consequence, it has been difficult to establish a routine clinical molecular diagnostic test for NF1.  Recently, however, an approach has been developed based on use of multiple complementary techniques to detect the various types of NF1 mutations(5).  This approach has a sensitivity of at least 95%, and is now offered on a routine clinical basis.  It can be helpful to resolve diagnostic uncertainty, but, with few exceptions, does not predict the course of the disorder.  Individuals with large deletions tend to have an unusually severe course, with early onset of large numbers of neurofibromas and increased risk of malignancy(6), but, otherwise, no genotype-phenotype correlations have been established.

Feature	Comments
Café-au-lait macules	At least 6 > 5mm prepubertal, 15 mm postpubertal; no correlation with disease severity
Skin-fold freckles	Appear between 3-5 years of age
Neurofibromas	At least 2 solitary or 1 plexiform
Optic glioma	Occur in 15% of affected children, usually between 2-6 years of age
Characteristic skeletal dysplasia	Tibial dysplasia, long bone dysplasia, orbital dysplasia
Lisch nodules	Melanocytic hamartomas, found on iris in 95% of adults with NF1
Affected 1st degree relative	NF1 is autosomal dominant trait with about 50% of cases arising by new mutation

Table 1.  Diagnostic criteria for NF1.
 
Management of NF1
Management of NF1 is focused on early detection of treatable complications, anticipatory guidance, and genetic counseling.  The mainstay of treatment remains surgical, although there is active research directed towards development of medical therapies (see below).  Some of the major complications are listed in Table 2. 

Neurofibromas can be isolated lesions on the skin or deeper in the body, or plexiform tumors.  The latter involve a length of a major nerve and its branches and can be infiltrative(7).  Plexiform neurofibromas can be associated with soft tissue hypertrophy.  Most are congenital, and grow over a period of time in the early childhood years.  The only existing treatment is surgical, but plexiform tumors usually cannot be fully resected and therefore often grow back.  Isolated neurofibromas can cause symptoms of nerve compression or may grow through the neural foramen to compress the spinal cord.  Dermal tumors are medically benign but can pose major cosmetic problems.  They can be removed through plastic surgery, laser treatments, or electrodessication.  The overall number of dermal neurofibromas is highly variable and unpredictable.  They tend to accumulate particularly during puberty and, in women, pregnancy. 

Approximatey 15% of children with NF1 develop optic gliomas(8).  The tumor may arise in the orbital or chiasmatic portions of the optic nerve.  The former are associated with proptosis, the latter with precocious puberty.  Optic gliomas are childhood lesions, usually appearing and progressing between about 2-6 years of age.  A high proportion are asymptomatic in spite of displaying radiographic signs of progression.  Symptomatic tumors are now treated with chemotherapy (vincristine and carboplatin), but most do not require any treatment.  There is controversy surrounding the use of MRI in asymptomatic children with NF1 to detect optic gliomas.  Current consensus guidelines do not recommend “baseline” scanning because of the frequent lack of associated symptoms and progression and the need to sedate young children to obtain scans.

The major malignancy associated with NF1 is malignant peripheral nerve sheath tumor (MPNST).  These are highly malignant sarcomas, usually arising within pre-existing plexiform neurofibromas.  The lifetime risk is about 10%(9).  Malignancies present with pain and sudden growth of a tumor, but there is often a delay in diagnosis given the typically large tumor burden of most patients.  Treatment is mainly surgical, with no clear evidence of benefit from radiation or chemotherapy.

The major skeletal dysplasia associated with NF1 are long bone dysplasias, especially involving the tibia, bone cysts, scoliosis, and orbital dysplasia(10).  Sphenoid dysplasia most commonly occurs in association with orbital plexiform neurofibroma.  Individually, skeletal disorders are relatively rare, but are important to recognize and manage to avoid later complications such as pseudoarthrosis.

Approximately 50% of individuals with NF1 experience some kind of learning problem(11).  Both verbal and nonverbal learning disabilities occur, with no NF1-specific pattern.  Some children exhibit more severe cognitive problems or developmental delay.  Attention deficit disorder with or without hyperactivity is also common.  There is evidence that the number of areas of enhanced T2 signal intensity in the brain correlates with learning disabilities, but the presence of these lesions is not predictive for clinical purposes.  These sites also tend to disappear with age, although the learning disabilities do not resolve(12).

Vascular complications are an important, and often overlooked, complication of NF1(13).  There can be an intimal proliferation in major arteries that can lead to renal artery stenosis and hypertension, dissection of major vessels, and carotid stenosis with consequent moya moya syndrome.  Pheochromocytoma can also be a cause of hypertension in NF1, but occurs only rarely.
 

System	Major Complications
Central nervous  system	Glioma (including optic glioma), macrocephaly, learning disability
Peripheral nervous system	Neurofibroma, plexiform neurofibroma, nerve compression
Skin	Cafe-au-lait spots, skin-fold freckling
Cardiovascular	Vascular stenosis, hypertension
Skeletal	Skeletal dysplasia, scoliosis, short stature
Endocrine	Precocious puberty, pheochromocytoma
Gastrointestinal	Obstruction due to neurofibromas
Hematological	Juvenile myelomonocytic leukemia

Table 2.  Major complications of NF1.

Frontiers in Clinical Research on NF1
The NF1 gene encodes a 3818 amino acid protein referred to as “neurofibromin(14).”  The protein includes a GTPase activating protein (GAP) domain, which regulates conversion of Ras-GTP to Ras-GDP.  Ras is a membrane-bound signal transduction molecule that is involved in regulation of cell growth.  The NF1 gene behaves as a tumor suppressor.  Individuals with NF1 are born with one mutated copy of the gene.  Loss of function of the other copy in specific Schwann cells leads to initiation of neurofibroma growth.  Neurofibromas consist of a mixture of multiple cell types, including Schwann cells, fibroblasts, perineurial cells, and mast cells. It is likely that most of these cells are stimulated to divide by cytokines, some of which may be produced by the Schwann cells that have lost neurofibromin function.  Malignant tumors such as MPNST arise by the accumulation of additional genetic damage, such as loss of TP53 gene function.

Several clinical trials have been undertaken for the treatment of NF1 (Table 3).  Current trials are tracked by the National Neurofibromatosis Foundation at www.nf.org/clinical_trials.  Drugs under test include angiogenesis inhibitors, inhibitors of fibroblast growth, and Ras inhibitors.  One of the major challenges in clinical trials is the difficulty in establishing endpoints for treatment.  Plexiform neurofibromas, the current target for clinical trials, tend to be large, irregularly shaped, and infiltrative.  Volumetric MRI is now being used to follow the growth of these tumors(15).  Dermal tumors may occur on the surface of the skin or within the dermis.  There is a need for imaging approaches to measure rate of change of these tumors.

Improved treatment of malignancy may await development of more effective therapeutic agents, but will also benefit from approaches to early detection.  These include imaging techniques that can distinguish malignant from nonmalignant tissue as well as surrogate markers, perhaps protein markers.  PET scanning has been used in the early detection of MPNST, but more data on sensitivity and specificity are needed(16).

Target	Therapeutics
Ras	Farnesyl protein transferase inhibitor (ongoing)
Angiogenesis	Interferon alpha 2a (trials concluded and ongoing; thalidomide
Fibroblasts	Pirfenidone (ongoing)
Mast cells	Ketotofin (trial concluded)
Hormones	Receptor antagonists (no trials)

Table 3.  Potential targets for NF1 therapeutics and examples of compounds currently or previously tested.

Conclusions
NF1 poses innumerable challenges, including diagnostic, management, patient education, and therapeutic.  Much has been learned in the “genomic era,” especially about disease pathogenesis.  It is hoped that advances both in imaging technology and in molecular genetics will continue to fuel advances that will lead to effective approaches to prevention and treatment of major complications.

Reference List

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